Chemical synthesis and biological evaluation of cis- and trans-12,13-cyclopropyl and 12,13-cyclobutyl epothilones and related pyridine side chain analogues

K. C. Nicolaou, K. Namoto, A. Ritzén, T. Ulven, M. Shoji, J. Li, G. D'Amico, D. Liotta, C. T. French, M. Wartmann, K. H. Altmann, P. Giannakakou

Research output: Contribution to journalArticle

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Abstract

The design, chemical synthesis, and biological evaluation of a series of cyclopropyl and cyclobutyl epothilone analogues (3-12, Figure 1) are described. The synthetic strategies toward these epothilones involved a Nozaki - Hiyama - Kishi coupling to form the C15 - C16 carbon - carbon bond, an aldol reaction to construct the C6 - C7 carbon - carbon bond, and a Yamaguchi macrolactonization to complete the required skeletal framework. Biological studies with the synthesized compounds led to the identification of epothilone analogues 3, 4, 7, 8, 9, and 11 as potent tubulin polymerization promoters and cytotoxic agents with (12R,13S,15S)-cyclopropyl 5-methylpyridine epothilone A (11) as the most powerful compound whose potencies (e.g. IC50 = 0.6 nM against the 1A9 ovarian carcinoma cell line) approach those of epothilone B. These investigations led to a number of important structure - activity relationships, including the conclusion that neither the epoxide nor the stereochemistry at C12 are essential, while the stereochemistry at both C13 and C15 are crucial for biological activity. These studies also confirmed the importance of both the cyclopropyl and 5-methylpyridine moieties in conferring potent and potentially clinically useful biological properties to the epothilone scaffold.

Original languageEnglish
Pages (from-to)9313-9323
Number of pages11
JournalJournal of the American Chemical Society
Volume123
Issue number38
DOIs
Publication statusPublished - 2001 Sep 26
Externally publishedYes

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Epothilones
Pyridine
Carbon
Stereochemistry
Tubulin Modulators
Lead compounds
Epoxy Compounds
Cytotoxins
Structure-Activity Relationship
Bioactivity
Scaffolds
Inhibitory Concentration 50
Polymerization
Cells
Carcinoma
Cell Line
pyridine

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Chemical synthesis and biological evaluation of cis- and trans-12,13-cyclopropyl and 12,13-cyclobutyl epothilones and related pyridine side chain analogues. / Nicolaou, K. C.; Namoto, K.; Ritzén, A.; Ulven, T.; Shoji, M.; Li, J.; D'Amico, G.; Liotta, D.; French, C. T.; Wartmann, M.; Altmann, K. H.; Giannakakou, P.

In: Journal of the American Chemical Society, Vol. 123, No. 38, 26.09.2001, p. 9313-9323.

Research output: Contribution to journalArticle

Nicolaou, KC, Namoto, K, Ritzén, A, Ulven, T, Shoji, M, Li, J, D'Amico, G, Liotta, D, French, CT, Wartmann, M, Altmann, KH & Giannakakou, P 2001, 'Chemical synthesis and biological evaluation of cis- and trans-12,13-cyclopropyl and 12,13-cyclobutyl epothilones and related pyridine side chain analogues', Journal of the American Chemical Society, vol. 123, no. 38, pp. 9313-9323. https://doi.org/10.1021/ja011338b
Nicolaou, K. C. ; Namoto, K. ; Ritzén, A. ; Ulven, T. ; Shoji, M. ; Li, J. ; D'Amico, G. ; Liotta, D. ; French, C. T. ; Wartmann, M. ; Altmann, K. H. ; Giannakakou, P. / Chemical synthesis and biological evaluation of cis- and trans-12,13-cyclopropyl and 12,13-cyclobutyl epothilones and related pyridine side chain analogues. In: Journal of the American Chemical Society. 2001 ; Vol. 123, No. 38. pp. 9313-9323.
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abstract = "The design, chemical synthesis, and biological evaluation of a series of cyclopropyl and cyclobutyl epothilone analogues (3-12, Figure 1) are described. The synthetic strategies toward these epothilones involved a Nozaki - Hiyama - Kishi coupling to form the C15 - C16 carbon - carbon bond, an aldol reaction to construct the C6 - C7 carbon - carbon bond, and a Yamaguchi macrolactonization to complete the required skeletal framework. Biological studies with the synthesized compounds led to the identification of epothilone analogues 3, 4, 7, 8, 9, and 11 as potent tubulin polymerization promoters and cytotoxic agents with (12R,13S,15S)-cyclopropyl 5-methylpyridine epothilone A (11) as the most powerful compound whose potencies (e.g. IC50 = 0.6 nM against the 1A9 ovarian carcinoma cell line) approach those of epothilone B. These investigations led to a number of important structure - activity relationships, including the conclusion that neither the epoxide nor the stereochemistry at C12 are essential, while the stereochemistry at both C13 and C15 are crucial for biological activity. These studies also confirmed the importance of both the cyclopropyl and 5-methylpyridine moieties in conferring potent and potentially clinically useful biological properties to the epothilone scaffold.",
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AU - Ritzén, A.

AU - Ulven, T.

AU - Shoji, M.

AU - Li, J.

AU - D'Amico, G.

AU - Liotta, D.

AU - French, C. T.

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AU - Altmann, K. H.

AU - Giannakakou, P.

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AB - The design, chemical synthesis, and biological evaluation of a series of cyclopropyl and cyclobutyl epothilone analogues (3-12, Figure 1) are described. The synthetic strategies toward these epothilones involved a Nozaki - Hiyama - Kishi coupling to form the C15 - C16 carbon - carbon bond, an aldol reaction to construct the C6 - C7 carbon - carbon bond, and a Yamaguchi macrolactonization to complete the required skeletal framework. Biological studies with the synthesized compounds led to the identification of epothilone analogues 3, 4, 7, 8, 9, and 11 as potent tubulin polymerization promoters and cytotoxic agents with (12R,13S,15S)-cyclopropyl 5-methylpyridine epothilone A (11) as the most powerful compound whose potencies (e.g. IC50 = 0.6 nM against the 1A9 ovarian carcinoma cell line) approach those of epothilone B. These investigations led to a number of important structure - activity relationships, including the conclusion that neither the epoxide nor the stereochemistry at C12 are essential, while the stereochemistry at both C13 and C15 are crucial for biological activity. These studies also confirmed the importance of both the cyclopropyl and 5-methylpyridine moieties in conferring potent and potentially clinically useful biological properties to the epothilone scaffold.

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